Treatment for dry eye syndrome

ABSTRACT

A novel formulation for the treatment of the many underlying inflammatory processes that cause dry eye syndrome. In particular, the formulation, which is orally administered includes the optimal blend of omega-3 and omega-6 essential fatty acids, and nutrient cofactors necessary to enhance the metabolic conversion associated with the tear-specific series E-one anti-inflammatory prostaglandin (PGE1). As used herein, the term “nutrient cofactor” refers to a compound that supports and enhances the conversion of linoleic acid to gamma-linolenic acid. Additionally, the formulation inhibits the production of pro-inflammatory compounds, as well as the growth of viral and bacterial pathogens of the three-layer tear film.

FIELD OF THE INVENTION

The present invention relates generally to the treatment of eyedisorders, and, in particular, to an orally administered treatment fordry eye syndrome.

BACKGROUND OF THE INVENTION

Sufficient lubricating tears are critical to good eye health. Becausetears provide the same functions for the cornea of the eye that theblood provides for the body, any abnormalities in tear production canresults in eye disorders. One such disorder is dry eye syndrome. Dry eyesyndrome, commonly referred to as “dry eyes,” is a prevalent eyecondition affecting approximately 20 million Americans. Specifically,dry eye syndrome is a disorder resulting generally from any abnormalityin the tear production process, such as decreased tear production,excessive tear evaporation, or an abnormality in mucin or lipidcomponent of the tear film that covers the normal ocular surface.

Although dry eye syndrome may have many different etiologies, the commondenominator in all cases of dry eye is that it involves changes in theocular surface due to alterations in the quality or quantity of tears.To understand the causes of dry eye syndrome, therefore, it is alsoimportant to understand the basics of tear production. The action oftears takes place in the three layers of the tear film. The mucin ormucus layer is the closest layer to the corneal epithelium. It isproduced by the conjuctival goblet cells, and is absorbed by the cornealsurface glycoproteins, creating a hydrophilic surface. Mucin deficiency,or mucopolysaccharide abnormalities, can lead to poor wetting orglycation of the corneal surface with subsequent desiccation andepithelial damage, even in the presence of adequate aqueous tearproduction. The aqueous layer, which floats on the mucin layer, issecreted by the lacrimal gland and incorporates all water-solublecomponents of the tear film. Further, the aqueous layer makes up 90% ofthe tear film's thickness. The significance of the aqueous layer is thatit provides moisture and supplies oxygen and important nutrients to thecornea of the eye. Finally, on the outside of the aqueous layer is thelipid layer. The lipid or oil layer is produced by the meibomian glandswith contributions from the glands of Zeis and Moll of the eye lids. Thesecretion of the lipid layer is an oily material, which is fluid at bodytemperature and retards the evaporation of the aqueous layer and lowerssurface tension, thereby allowing the tear-film to adhere to the eye'ssurface. Androgen receptors are located in both the lacrimal andmeibomian glands. A decrease in circulating androgen hormones can resultin loss of the oil layer, which exacerbates the evaporative tear loss.

The ocular surface is bathed in tears that provide nutrients,lubrication, and information about chemical regulators to the cells ofthe corneal and conjunctiva. Tears are needed to maintain the normalocular surface as well as to repair injury and surgical trauma The blinkreflex renews the tear film by delivering aqueous and lipid to the tearfilm and sweeping away debris. The normal blink interval is about 5seconds under normal conditions. The tear film is typically stable forabout 10 seconds. Tears are normally evaporated or forced out throughthe nasolacrimal ducts in the inner corner of the eyes on blinking.

Optimum ocular functioning requires essential fatty acids (EFAs).Because EFAs cannot be synthesized by the human body, they must beobtained from the diet. In particular, the omega-6 essential fatty acid,linoleic acid, is significant to dry eye syndrome. The body convertslinoleic acid into series one prostaglandins (PGE1) by first convertingit into gamma-linolenic acid (GLA), next into dihomo-gamma-linolenicacid, and finally into PGE1. PGE1 is important for lacrimal and salivarygland secretion and for T cell function. T cells are an essentialelement of the body's immune system, and the disruption of theirfunctioning can contribute to the onset of diseases causing dry eyesyndrome.

It is also important in the formation of PGE1 that the omega-6 essentialfatty acids be in balance with omega-3 fatty acids. Omega-3 fatty acidshelp to prevent the metabolism of omega-6 fatty acids intopro-inflammatory compounds, thereby further enhancing the formation ofPGE1. A disruption in this overall process is also believed to be anunderlying cause of dry eye syndrome.

The typical symptoms of the dry eye syndrome include dryness,grittiness, irritation, difficulty reading for long periods of time,burning, and even the apparent contradiction of excessive tearing orwatering. In extreme cases of dry eye, patients may become unusuallysensitive to light, experience severe eye pain, and start to noticediminished vision. Successful treatment may be needed to avoid permanentdamage.

These symptoms can result from many different causes of dry eyesyndrome. Like most eye conditions, dry eye syndrome is often related tohealth conditions in the rest of the body, including dryness of othermucus membranes such as those located in the mount, vagina, and joints.Dry eye syndrome can also be a sign of digestive imbalances or of moreserious systemic autoimmune diseases, such as rheumatoid arthritis,Sjogrens syndrome or lupus erthematosus. Other disorders, such asdiabetes, glaucoma, thyroid disease, and blepharitis are also believedto be related to dry eye syndrome.

The causes of dry syndrome can be categorized based on which area orlayer of the tear film is affected. Lubricant deficient dry eyeencompasses disorders of the mucin layer and goblet cells. Thesedisorders typically arise from vitamin A deficiency, proteinmalnutrition, conjunctival shrinkage, viral infections, thermal damage,irradiation damage, chemical injury, chemical preservatives, allergicconjunctivitis, and an increase in tear film osmolarity from lipid oraqueous dysfunction.

Aqueous tear-deficient dry eye encompasses disorders of the aqueouslayer of the tear film. Tear deficient dry eye involves a decrease inthe output of the lacrimal glands producing aqueous tears. This categorycan be further subdivided into Sjogrens-associated andnon-Sjogrens-associated dry eye. Evidence exists that indicates that dryeye of both the Sjogrens and non-Sjogrens types has an inflanmmatorycomponent that is an important feature in the pathogenesis of ocularsurface disease. Sjogrens syndrome involves systems other than the eyeincluding dry mouth, arthralgia, rheumatoid arthritis, and scleroderma.Non-Sjogrens aqueous deficiency, on the other hand, may be caused by agerelated atrophy of the lacrimal glands. The normal aging of tear glands,for example, can result in dryness, because tear volume decreases fromage 18 as much as 60% by age 65. Further causes include isolated KCS,pharmaceuticals, menopause, noxious agents, damage to the lacrimalgland, and chronic viral infection.

Evaporative dry eye encompasses disorders of the lipid layer.Evaporative dry eye is characterized by excessive evaporative loss oftears from the ocular surface. The form most commonly encountered inclinical practice is meibomian gland dysfunction, which is characterizedby a blockage of the mebomian glands and qualitative changes in thenature of their oily secretion. In normal eyes, lipids from themeibomian glands, and to a lesser extent the Moll and Zeiss glands,retard the evaporation of tears. Changes in the quality or quantity oftear lipids diminish the ability of the lipid layer to slow evaporationand maintain the integrity of the tear film. Both animal and humanstudies suggest that the pathogenesis of dysfunction of the lacrimal andmeibomian glands may be linked. As is the case with aqueoustear-deficient dry eye, surface inflammation is a feature of evaporativedry eye and may play a role in both pathogenesis and symptomatology.Common causes for evaporative dry eye lipid layer disorders are aging,meibomianitis, and environmental conditions, such as the “sick office”syndrome, dry and/or windy climate, pollutants, and air conditioning.Computer use can also cause dry eye, as most people blink lessfrequently (about 7 times per minute vs. a normal rate of around 22times/minute) that leads to increased evaporation along with fatigue andeye-strain associated with staring at a computer monitor.

It has now been clearly shown that a neural feedback mechanism linksnerve endings on the ocular surface to the lacrimal glands. In responseto neural stimulation, the lacrimal glands secrete a variety ofcomponents, including a number of small natural antibiotic proteins,like lactoferrin, an iron-binding protein released by neutrophils, andthe neurotransmitter, acetylcholine which all play a significant role incontrolling the turnover of epithelial cells on the corneal andconjunctival surfaces. The ocular surface nerve endings and the neuralpathway are also important to the maintenance of a healthy ocularsurface and the eye's ability to respond to injury.

Accordingly, the disruption of nerve endings on the ocular surface isalso believed to cause dry eye syndrome. An example of this type ofdisruption occurs as a result of LASIK surgery. In LASIK surgery, up to70% of the superficial comeal nerve endings are severed during flapcreation. LASIK also introduces the following factors that can disruptthe sensory and autonomic neural connections that unify and drive thetightly integrated ocular surface/lacrimal/meibomian gland system: liddamage caused by the speculum, surgical induced fee radical production,decreased tear production, depressed corneal and conjunctival sensation,abnormal tear clearance, increase of inflammatory factors on ocularsurface, and exacerbation of preoperative, possibly sub clinical, dryeye.

Inflammation of the ocular surface may also disturb the nerve endings,which in turn would disrupt the neural feedback mechanism and adverselyaffect tear production and cellular renewal. Sensation plays a criticalrole in initiating blink, as well. With compromised sensation, the blinkrate can slow to the point where the tear film breaks up before the nextblink can reconstitute it. The resultant absence of tear film willexpose the epithelial surface to drying, mechanical damage, and therelease of agonal chemicals from within the cells. This result initiatesan inflammatory process. Even minimal levels of dry eye will result in alow-level ocular surface inflammatory component. If left untreated,smoldering inflammation can cause damage over time and increasesusceptibility to bacterial conjunctivitis and viral conjunctivitis.

Most physicians recognize the underlying inflammatory process that is apart of dry eye in general and post-LASIK and other surgical induced dryeye. One cannot cut into tissue without causing the release ofpro-inflammatory mediators and the diffusion of inflammatory cells tothe incision. Proper blinking is necessary to distribute the top oilylayer of the tear film. Surgery causes an alteration in the ability ofthe lid and tear film to protect the ocular surface. As a result,epithelial cells die at a greater rate and release chemicals, whichcause damage and inflammation.

Additional causes of dry eye syndrome include the following. Extendeduse of contact lens can result in dry eye from corneal oxygen andnutrient deficiency. Protein build-up on contact lens can produce abreeding ground for bacterial growth and surface roughness, furthercontributing to inflammatory changes. Also, medications such asantibiotics, blood pressure medications, antidepressants, diuretics,over-the-counter vasoconstrictors, antihistamines, birth control pills,appetite suppressants, and ulcer medications, refractive surgery,autoimmune diseases and disorders such as those mentioned above,hormonal changes, and nutritional deficiencies can cause disruption inthe tear production and retention process.

The conventional treatment for dry eyes involves treating the symptomsrather than the cause. For example, artificial tears and ocularlubricants are a common treatment. Although artificial tears may providetemporary relief, they merely palliate the symptoms. Furthermore, thepreservatives used in the artificial tears can actually aggravate thecondition, and can even kill corneal cells. Artificial tears thatpromise to “get the red out” actually reduce circulation in the eye byvessel constriction, decreasing production of the tear film, and worse,eventually make the eyes drier. The “rebound” dilation of surfacevessels further contributes to the inflammatory response.

Another form of treatment is punctal occlusion. Punctal occlusion is aprocedure used to help dry eye patients by closing the tear drainagecanals with silicone plugs, which keep most of the fluid from drainingaway from the surface of the eye. This may provide long-term relief.

Thus far, there have been few approaches to the treatment of dry eyedisorders that have been effective in addressing all the issuesregarding dry eye syndrome. The present applicant previously developed aformulation, which is described in the specification of U.S. Pat. No.6,506,412 and sold under the trademark HYDROEYE®, for treating theunderlying inflammatory processes that cause dry eye syndrome. However,the HYDROEYE® treatment focused only on the production of theanti-inflammatory PGE1 and mucin. Although inflammation is still themain concern in dry eye syndrome, site-specific anti-inflammatoryprostaglandins only address part of the dry eye inflammatory process.For example, the formulation did not address the inhibition ofpro-inflammatory compounds, such as PGE2 and Interleukin-1. Further, theformulation did not address the inhibition of the growth of viral andbacterial pathogens in the three-layer tear film through the productionof lactoferrin, which is a natural antibiotic.

Accordingly, there remains a need for an improved formulation thataddresses a wider range of the underlying inflammatory processes thatcause dry eye syndrome.

SUMMARY OF THE INVENTION

According to its major aspects and briefly recited, the presentinvention is a novel formulation for the treatment of the manyunderlying inflammatory processes that cause dry eye syndrome. Inparticular, the formulation, which is orally administered includes theoptimal blend of omega-3 and omega-6 essential fatty acids, and nutrientcofactors necessary to enhance the metabolic conversion associated withthe tear-specific series E-one anti-inflammatory prostaglandin (PGE1).As used herein the term “nutrient cofactor” refers to a compound thatsupports and enhances the conversion of linoleic acid to gamma-linolenicacid. Additionally, the present formulation inhibits the production ofpro-inflammatory compounds, as well as the growth of viral and bacterialpathogens of the three-layer tear film.

In a first embodiment, the formulation includes the following compoundsor ingredients: 1) black currant seed oil, as a source of omega-3 andomega-6 essential fatty acids (EFAs), as well as gamma-linolenic-acid(GLA); 2) cod liver oil, as a source of omega-3 fatty acid,docosahexaeonic acid (DHA) and eicosapentaenoic acid (EPA); 3) vitaminE, as a mixture of d-alpha tocopherol and dl-alpha tocopherol,containing gamma tocopherol; 4) vitamin A, as retinal palmitate; 5)vitamin B6, as pyridoxal 5-phosphate; 6) magnesium, as magnesiumsulfate; 7) vitamin C, as calcium ascorbate and ascorbic acid; 8)curcumin, as turmeric extract; 9) lactoferrin; and 10) mucin complex, asmucopolysaccharides.

In a second embodiment, any or all of the following ingredients arecombined with the above-described formulation to impart particularfeatures to the formulation: 1) L-carnitine; 2) DHEA(dehydroepiandrosterone); and 3) beta-glucan.

A unique feature of the present invention is the use of vitamin E inproper combination with the other components of the formulation. VitaminE is an important regulator of prostaglandin E2 (PGE2), which plays akey role in inflammation and diseases associated with inflammation.Specifically, vitamin E inhibits cyclooxygenase-2 (COX-2) enzymeactivity that promotes inflammatory response by catalyzing the synthesisof PGE2. Further, vitamin E enhances the T-cell function needed toinhibit the production of the pro-inflammatory Interleukin-1, which isresponsible for inhibiting lacrimal aqueous secretion. Finally, vitaminstabilizes and prevents the oxidation of the omega-3 and omega-6 EFAsthat are needed to generate anti-inflammatory PGE1.

Another feature of the present invention is the use of curcumin incombination with the other components of the formulation. Curcumininhibits the expression and activity of the COX-2 enzyme involved in theproduction of inflammatory symptoms in the dry eye syndrome. Aspreviously discussed, COX-2 is a necessary catalyst for the formation ofthe pro-inflammatory PGE2 and Interleukin-1. Specifically, curcumin is anatural COX-2 inhibitor with similar chemical properties to ibuprofens,such as those sold under the trademarks MOTRIN® and ADVIL®. Thedifference between these products and curcumin is that curcumin does notinhibit production of the COX-1 enzyme that is necessary to protect thestomach lining.

Yet another feature of the present invention is the use ofAPO-lactoferrin (“lactoferrin”) in combination with the other componentsof the formulation. Lactoferrin, a glycoprotein present in milk, mucosalsecretions and neutrophils, is a natural antibiotic that inhibits viraland bacterial infections through its ability to bind iron, and furtherbalances other tear lipocalins (family of proteins that transport smallhydrophobic molecules), which modulate the surface tension of the tearfilm and affect the comfort of the contact lens wearer. Because bothbacteria and viruses depend on iron to grow, the inclusion oflactoferrin, which binds iron, helps to starve and inhibit theseinfections. Tear lipocalins (TLs) are the major lipid-binding protein intears, and are able to increase the surface pressure of aqueous layer byscavenging lipids from hydrophobic surfaces and delivering them to theaqueous phase of the tear film. By introducing lactoferrin to the eye,the formulation helps to stimulate additional production of lactoferrinby the body. Without such an addition of lactoferrin, the production oflactoferrin by the body remains dependent on the gamma-linolenic-acidmetabolite prostaglandins to signal the neutrophils in the aqueous andlipid layers of the tear film to produce lactoferrin.

Still another feature of the present invention is the use of L-carnitinein combination with the other components of the formulation. L-carnitineis an amino acid that serves as a cellular nutrient transport deliverymedium for the movement the EFAs across the mitochondria.

The use of DHEA in combination with the other components of theformulation is yet another feature of the present invention. DHEA playsan important role in supporting lacrimal gland secretory function andincreasing beta-andrenergic receptor binding sites. As hormone loss isbelieved to be a contributing factor to dry eye syndrome, the additionof hormones to the formulation enhances the effectiveness of the dry eyetreatment.

Still another feature of the present invention is the use of beta-glucanin combination with the other components of the formulation. Beta-glucanacts as an immune system modulator and potentiator of the macrophagereceptor sites by helping to modulate the T-cell/B-cell ratio. Further,beta-glucan reduces the production of Interleukin-1, a metabolite of thepro-inflammatory PGE2. Finally, beta-glucan enhances the immune responseproduction of secretory IgA (protein immunoglobulin A) and IgE (proteinimmunoglobulin E), thereby inhibiting the binding of microorganisms tomucosal surfaces and inhibiting mast cell histamine mediatedinflammatory response in the allergic dry eye.

Yet another feature of the present invention is the use of a synergisticblend of specific antioxidant components that stimulate and supportnormal functioning of oil and mucin secreting glands of the eyes aperiorbita. This synergistic blend provides a means of restoring normaloil, mucous and tear secretions of the eye to relieve the condition ofdry eye syndrome.

Still another feature of the present invention is the use of lubricantenhancing elements that are administered orally. A dietary nutritionalsupplement is administered to stimulate the natural production oflubricants as opposed to the use of superficial treatments for thesymptoms of dry eye by administration of topical lubricants (eye drops).

Another feature of the present invention is the use a formulation forrestoring normal lubrication to parts of the body affected by thenutritional deficiency of oil and mucin secreting glands, including, butnot limited to, the mouth, vagina, joints and synovia.

Still another feature of the present invention is the use of formulationfor relieving chronic inflammatory changes of the eye due to lack ofspecific anti-inflammatory components in the lacrimal and oil glandsecretions.

Yet another feature of the present invention is the use of a synergisticblend of components in a stable, slowly oxidizable form for more assuredpotency.

Still another feature of the present invention is the use of bothblandualr stimulants and anti-inflammatory components in one orallyadministered formulation.

Another feature of the present invention is the use of an immune systemmodulator to reduce the production of Interleukin 1 (IL-1), a metaboliteof the pro-inflammatory PGE2, thereby lessening the need for potentiallydangerous corticosteroids, which are now commonly used to reduce theIL-1 inflammatory process in the dry eye patient.

Still another feature of the present invention is the use of a treatmentfor dry eye syndrome by physiologic rather than pharmacologic means.

Other features and advantages of the present invention will be apparentto those skilled in the art from a careful reading of the DetailedDescription of the Preferred Embodiment presented below and accompaniedby the drawing.

BRIEF DESCRIPTION OF THE DRAWING

In The Drawing,

FIG. 1 is a schematic view of the metabolic pathways of omega-3 andomega-6 essential fatty acids according to a preferred embodiment of thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is an improved formulation for the treatment ofthe underlying inflammatory processes that cause dry eye syndrome.Through the oral administration of a blend of omega-3 and omega-6essential fatty acids, and nutrient cofactors necessary to enhance themetabolic conversion associated with the tear-specific series E-oneanti-inflammatory prostaglandin (PGE1), the root causes of dry eyesyndrome are addressed. Additionally, the formulation inhibits theproduction of pro-inflammatory compounds, as well as the growth of viraland bacterial pathogens of the three-layer tear film. Although thisparticular formulation is described in connection with the treatment ofhuman dry eye syndrome, it is also intended that the formulation andcould also be used for the treatment of dry eye syndrome among variousanimals, such as dogs. [It is known that various animals having, for themost part, a similar physiology of the eye to the human eye also sufferfrom dry eye syndrome. Accordingly, the formulation of the presentinvention is also effective at treating dry eye syndrome among thesevarious animals. Although, the effective amounts needed for thetreatment vary between humans and animals, one skilled in the art candetermine the differences in the effective amounts based on theparticular size of the animals.]

In a first preferred embodiment, the formulation includes the followingcomponents along with the preferred ranges of amounts for eachcomponent: Vitamin A (as retinyl 1000 IU (or a range of 500 IU to 1600IU) palmitate) Vitamin C 100 mg (or a range of 30 mg to 400 mg) (asCalcium ascorbate and Ascorbyl Palmitate) Vitamin E (as mixed 32 IU (ora range of 10 IU to 200 IU) tocopherols oil) Vitamin B6 (as pyridoxal- 8mg (or a range of 4 mg to 30 mg) 5-phosphate) Magnesium (as magnesium 20mg (or a range of 10 mg to 200 mg) sulfate) Black currant seed oil 00 mg(or a range of 400 to 2500 mg) Cod liver oil 2 mg (or a range of 1 mg to7 mg) Mucopolysaccarides (mucin 250 mg (or a range of 50 mg to 400 mg)complex) Turmeric (Curcuma longa) 100 mg (or a range of 20 mg to 300 mg)extract (root) Lactoferrin 10 mg (or a range of 5 mg to 200 mg)

In a second preferred embodiment, other components can be included toimpart additional features to the formulation. Specifically, thecompents L-carnitine, DHEA, and beta-glucan can be included into theabove-described formulation either in combination or separately. Thefollowing is a list of the preferred ranges of these additionalcomponents that are included in combination with the above-describedformulation: L-carnitine 100 mg (or a range of 10 mg to 1000 mg) DHEA 10mg (or a range of 1 mg to 100 mg) beta-glucan 100 mg (or a range of 10mg to 1000 mg)

Although varying amounts of each component are contemplated by timepresent invention, the listed ranges are the approximate preferredranges based on the necessary functions of each component in thetreatment of dry eye syndrome. The formulation as described ispreferably administered orally to a patient in a capsule form twicedaily as a dietary supplement, wherein the patient takes two capsuleswith a morning meal and two capsules with an evening meal.

In order to understand the mechanism of action of the above describedformulation, it is important to also understand the metabolic pathwaysof two of the key components of the formulation: omega-3 and omega-6essential fatty acids (EFAs). Accordingly, FIG. 1 illustrates thesemetabolic pathways. As shown, omega-6 fatty acids metabolize to thesite-specific anti-inflammatory, series E1 prostaglandin (PGE1), whichsystemically supports proper tear function. The series E1 prostaglandinsaugment eicosanoid (specific white blood cells) levels and therebyrelieves chronic inflammation, which is a systemic cause of dry eyesyndrome. PGE1 is beneficial in inhibiting inflammation in all mucosaltissue, and it is a particularly efficacious anti-inflammatory in bothtears and saliva. Not only does PGE1 reduce ocular surface inflammation,but also the inflammatory process associated with meibomitis and reducedlacrimal gland aqueous output.

Omega-6 fatty acids convert to PGE1 via the linoleic-acid (LA) togamma-linolenic-acid (GLA) to dihomo-gamma-linolenic-acid (DGLA) to theseries E-one prostaglandins (PGE1). To ensure this conversion to PGE1,the nutrient cofactors, vitamins A, C, B6, and magnesium were alsoincluded in the formulation. The delta-6-desaturase (D6D) enzymenecessary for this conversion is too easily disrupted by such agents asalcohol, aging, smoking, elevated cholesterol levels, viral infections,cardiovascular disease, hormonal fluctuations, sugar consumptions,chemical carcinogens, and environmental factors without these additionalnutrient cofactors. Advantageously, these nutrient cofactors alsomodulate goblet cell production, lacrimal gland aqueous tear production,meibomian gland function, and neurotransmitter blink response.

However, the formation of PGE1 is only a portion of the dry eyeinflammatory process needed to be addressed for effective treatment. Forexample, the production of pro-inflammatory compounds is also anunderlying inflammatory process that needs to be inhibited for effectivetreatment of dry eye syndrome. As shown in FIG. 1, if PGE1 is not formedand DGLA is metabolized into arachidonic acid, pro-inflammatorycompounds such as PGE2 and LTB4 (Leukotriene B4) are formed.Accordingly, the present invention blocks the formation of arachidonicacid with the addition of vitamin E gamma tocopherols, EPA(eicosapentaenoic acid) from cod liver oil, and curcumin. Additionally,anti-inflammatory compounds such as PGE3 and LTB5, which are produceddownstream of the metabolic pathway of omega-3 fatty acids, furthercontribute to an enhanced treatment of dry eye syndrome.

The formulation further includes components that inhibit viral andbacterial infections that affect the tear film and contribute to dry eyesyndrome. Specifically, the formulation includes apo-lactoferrin, whichincreases the aqueous level of iron binding proteins and helps tomodulate the surface tension of the tear film.

The following discusses the components of the above describedformulation and explains their respective functions in the treatment ofdry eye syndome:

Black currant seed oil provides both linoleic acid andgamma-linolenic-acid (GLA) from omega-3 and omega-6 EFAs, which are themetabolic precursors to PGE1. Biochemically, black currant seed oil isthe most stable source of linoleic acid. Furthermore, black currant seedoil contains 18% GLA, which converts to anti-inflammatory PGE1 with theaid of the other nutrient cofactors vitamins A, C, B6, and magnesium.Omega-3 fatty acid, omega-6 fatty acid and GLA together make upapproximately 31% of black currant seed oil.

Cod liver oil, which is preferably pharmaceutical grade, provides thenecessary omega-3 fatty acid, docosahexaeonic acid (DHA) to balance theblack current seed oil omega-6s ratio for the consistent metabolism ofthe anti-inflammatory PGE1. To further insure the omega-6 downstreamconversion to PGE1, DHA/EPA omega-3 fatty acids inhibit thedelta-5-desaturase (D5D) enzymatic metabolic conversion to arachidonicacid (AA), which can convert to pro-inflammatory cyclooxygenase-2(COX-2) and prostaglandin E2, as well as LTB4. Additionally, omega-3serves as a metabolic gateway boost to the downstream conversion of theomega-3 to the anti-inflammatory compounds, PGE3 and LTB5. Othercold-water fish oils can be used, but cod liver oil is preferred.

Vitamin A, as retinal palmitate, in proper combination with the othercomponents of the formulation helps stabilize delta-6-desaturase, whichis necessary for the formation of PGE1. Vitamin A additionally regulatesthe proliferation of corneal epithelial cells and preserves gobletcells. It is also required for the synthesis of mucin glycoproteins inthe eye. A deficiency of vitamin A can result in abnormal epithelialcells in the eyelids, lacrimal glands, and conjunctiva. Finally, vitaminA deficiency can also produce abnormalities of the precorneal tear filmand tear glands, and induce the occurrence of dry eye syndrome.

Vitamin C, as ascorbic acid and fat-soluble absorbyl palmitate, alsohelps to stablize D6D, which is required for the downstream conversionof omega-6 linoleic acid to PGE1. Preferably, there is 50% ascorbic acidand 50% absorbyl palmitate in the vitamin C. Further, because of theextended half-life of the fat soluble vitamin C over water-solubleascorbic acid, vitamin C consistently modulates PGE1 synthesis. Thecombination of vitamin C with the other components of the formulationalso enhances the production of IgE concentrates in tears, the firstline of basophil and mast cell defense against invading pathogens andallergens that frequently cause dry eye symptoms.

Vitamin B6, as pyridoxal-5-phosphate, is yet another necessary nutrientcofactor for the stabilization of D6D. Pyridoxal-5-phosphate is theactive form of vitamin B6.

Magnesium, as magnesium sulfate having 20% magnesium, is anotheressential cofactor in the conversion of linoleic acid into GLA.

Mucin complex, or mucopolysaccarides, provides mucin glycoproteins forthe maintenance of the mucin network layer in the tear film.

Vitamin E, as a mixture of d-alpha tocopherol and dl-alpha tocopherol,containing gamma tocopherol, is an important regulator of prostaglandinE2 (PGE2), which plays a key role in inflammation and diseasesassociated with inflammation. Preferably, the vitamin E mixture containsan equal amount of both d-alpha tocopherol and dl-alpha tocopherol.Specifically, vitamin E inhibits cyclooxygenase-2 (COX-2) enzymeactivity that promotes inflammatory response by catalyzing the synthesisof PGE2. Further, vitamin E enhances the T-cell function needed toinhibit the production of the pro-inflammatory Interleukin-1, which isresponsible for inhibiting lacrimal aqueous secretion. Finally, vitaminE stabilizes and prevents the oxidation of the omega-3 and omega-6 EFAsthat are needed to generate anti-inflammatory PGE 1.

Apo-lactoferrin, a glycoprotein present in milk, mucosal secretions andneutrophils, inhibits viral and bacterial infections through its abilityto bind iron, and further balances other tear lipocalins (family ofproteins that transport small hydrophobic molecules), which modulate thesurface tension of the tear film and affect the comfort of the contactlens wearer. Tear lipocalins (TLs) are the major lipid-binding proteinin tears, and are able to increase the surface pressure of aqueous layerby scavenging lipids from hydrophobic surfaces and delivering them tothe aqueous phase of the tear film.

L-carnitine is an amino acid that serves as a cellular nutrienttransport delivery medium for the movement the EFAs across themitochondria.

DHEA plays an important role in supporting lacrimal gland secretoryfunction and increasing beta-andrenergic receptor binding sites.

Beta-glucan acts as an immune system modulator and potentiator of themacrophage receptor sites by helping to balance the T-cell/B-cell ratio.Further, beta-glucan reduces the production of Interleukin-l, ametabolite of the pro-inflammatory PGE2. Finally, beta-glucan enhancesthe immune response production of secretory IgA and IgE, which inhibitsthe binding of microorganisms to mucosal surfaces and inhibits mast cellhistamine mediated inflammatory response in the allergic dry eye.

It will be apparent to those skilled in the art that many changes andsubstitutions can be made to the preferred embodiment herein describedwithout departing from the spirit and scope of the present invention asdefied by the appended claims.

1. A formulation for the oral treatment of dry eye syndrome, comprising:an effective amount of omega-3 fatty acid; an effective amount ofomega-6 fatty acid; an effective amount of gamma-linolenic-acid; aneffective amount of nutrient cofactors an effective amount oflactoferrin; an effective amount of mucin complex; an effective amountof vitamin E; and an effective amount of curcumin.
 2. The formulation asrecited in claim 1, further comprising an effective amount of DHEA. 3.The formulation as recited in claim 1, further comprising an effectiveamount of 1-carnitine.
 4. The formulation as recited in claim 1, furthercomprising an effective amount of beta-glucan.
 5. The formulation asrecited in claim 1, wherein said nutrient cofactors are selected fromthe group consisting of vitamin A, vitamin B6, vitamin C, magnesium, andany combination thereof.
 6. The formulation as recited in claim 1,wherein said omega-3 fatty acid is provided by cod liver oil.
 7. Theformulation as recited in claim 1, wherein said omega-6 fatty acid isprovided by black currant seed oil.
 8. The formulation as recited inclaim 1, wherein said gamma-linonlenic-acid is provided by black currantseed oil.
 9. The formulation as recited in claim 1, wherein said vitaminE is a mixture
 10. The formulation as recited in claim 1, wherein saidcurcumin is provided by turmeric extract.
 11. A formulation for thetreatment of dry eye syndrome, comprising: black currant seed oil, in arange of 400 mg to 2500 mg; cod liver oil, in a range of 1 mg to 7 mg,wherein the ratio between said black currant seed oil to said cod liveroil is 400 mg/1 mg; vitamin A, in a range of 500 IU to 1600 IU; vitaminC, in a range of 30 mg to 400 mg; vitamin B6, in a range of 4 mg to 30mg; lactoferrin, in a range of 5 mg to 400 mg; magnesium, in a range of10 mg to 200 mg; mucin complex, in a range of 50 mg to 400 mg; vitaminE, in a range of 10 IU to 200 IU; and curcumin, in a range of 20 mg to300 mg.
 12. The formulation as recited in claim 11, further comprisingDHEA, in a range of 1 mg to 100 mg.
 13. The formulation as recited inclaim 11, further comprising 1-carnitine, in a range of 1 mg to 100 mg.14. The formulation as recited in claim 11, further comprisingbeta-glucan, 10 mg to 1000 mg.
 15. The formulation as recited in claim11, wherein said vitamin C is a blend of 50% calcium ascorbate and 50%ascorbyl palmitate.
 16. The formulation as recited in claim 11, whereinsaid vitamin E is a mixture of 50% d-alpha tocopherol and 50% dl-alphatocopherol containing gamma tocopherol.
 17. A formulation for thetreatment of dry eye syndrome, comprising: black currant seed oil, atleast about 800 mg; cod liver oil, at least about 2 mg; vitamin A, atleast about 1000 IU; vitamin C, at least about 100 mg; vitamin B6, atleast about 8 mg; lactoferrin, at least about 10 mg; magnesium, at leastabout 20 mg; mucin complex, at least about 250 mg; vitamin E, at leastabout 32 IU; and curcumin, at least about 100 mg.
 18. The formulation asrecited in claim 17, further comprising DHEA, at least about 10 mg. 19.The formulation as recited in claim 17, further comprising 1-carnitine,at least about 100 mg.
 20. The formulation as recited in claim 17,further comprising beta-glucan, at least about 100 mg.